Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73, or A2-73) is a compound which is believed to bind to muscarinic acetylcholine and sigma-1 receptors with affinities in the low micromolar range. It has been reported that A2-73 showed neuroprotective potential against amyloid toxicity in mice. In particular, A2-73 has been reported as attenuating oxidative stress, caspases induction, cellular loss and learning and memory deficits observed in mice one week after the icy injection of an oligomeric preparation of amyloid β25-35 peptide (Aβ25-35) (Villard et al., J Psychopharmacol 2011). More recently, it has been reported that A2-73 blocked the Aβ25-35-induced P-Akt decrease and P-GSK-3β increase, indicating activation of the PI3K neuroprotective pathway (Lahmy et al., Neuropsychopharmacology, 2013). In the dose-range tested, A2-73 attenuated the hyperphosphorylation of Tau on physiological epitopes (AT-8 antibody clone) and on pathological epitopes (AT-100 clone). ANAVEX2-73 also has been reported decreasing the Aβ25-35-induced endogenous Aβ1-42 seeding.
A series of aminotetrahydrofuran compounds have been reported as exhibiting anti-amnesic, anticonvulsant, antidepressant and neuroprotective activities.1-4 Among them, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73) is a mixed muscarinic/σ1 protein profile, but with better selectivity for the σ1 subtype as compared with σ2 sites.1 Reported binding analyses showed an IC50=860 nM for σ1 and no affinity for σ2 sites. Moreover, the screening profile showed micromolar affinities for muscarinic M1-M4 receptors (IC50=3.3-5.2 μM), sodium channel site 2 (IC50=5.1 μM), and NMDA receptors (IC50=8.0 μM).
Reference is made to donepezil
Donepezil (or DPZ) is reported to be a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the symptomatic palliative treatment of mild to moderate Alzheimer's disease.
Reference is made to Memantine
Memantine is reported to act on the glutamatergic system by blocking NMDA-type glutamate receptors.
Reference is made to Galantamine
Galantamine is described as a competitive and reversible cholinesterase inhibitor.
Reference is made to Rivastigmine
Rivastigmine, an acetylcholinesterase inhibitor, believed to inhibit both butyrylcholinesterase and acetylcholinesterase.
Reference is made to the following publications, the teachings of which are incorporated by reference in their entirety.    1Vamvakides (2002) Ann Pharm Fr 60:88-92;    2Vamvakides (2002) Ann Pharm Fr 60:415-22;    3Espallergues et al. (2007) Br J Pharmacol 152:267-79;    4Villard et al (2009) Neuropsychopharmacology 34:1552-66;    5Maurice et al. (1996) Brain Res 706:181-93;    6Zussy et al. (2011) Am J Pathol 179:315-34;    7Hayashi & Su (2007) Cell 131:596-610;    8Su et al. (2010) Trends Pharmacol Sci 31:557-566;    9Meunier et al. (2006) Br J Pharmacol 149:998-1012.
Further noted are European Patent Application No. 08 702 158.0, “New Sigma-Receptor Ligands with Anti-Apoptotic and/or Pro-Apoptotic Properties Over Cellular Biochemical Mechanisms, With Neuroprotective, Anti-Cancer, Anti-Metastic and Anti-(Chronic) Inflammatory Action (also, U.S. Ser. No. 12/522,761), and U.S. Ser. No. 13/201,271, “Sigma Receptors Ligands With Anti-Apoptotic And/Or Pro-Apoptotic Properties, Over Cellular
Dovey et al., Mechanisms, Exhibiting Prototypical Cytoprotective And Also Anticancer Activity, Journal of Neurochemistry, 76(1) 173-181 (2001). Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain All publications cited herein are incorporated by reference in their entirety.